Psilocybin & MDMA: Inflammation, Stress & Brain-Body Communication | Michael Wheeler | 230

May 20, 2025

Dr. Michael Wheeler, an Assistant Professor of Neurology at Harvard Medical School, delves into the fascinating interplay between the immune system and the brain. He discusses how the blood-brain barrier allows immune signals to influence brain function, particularly in cases of chronic stress and depression. Wheeler explores the therapeutic potential of psychedelics like psilocybin and MDMA, highlighting their role in reducing inflammation and reshaping neuroimmune interactions. The discussion unveils insights into how these substances may offer hope for treatment-resistant mood disorders.

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INSIGHT

Blood-Brain Barrier and Stress

The brain's blood-brain barrier is not completely impermeable to immune signals even in healthy conditions.
Chronic stress can weaken this barrier, increasing neuroinflammation and impacting mood-regulating brain circuits.

INSIGHT

Brain Encoding of Immune Signals

The brain encodes peripheral immune signals through specific neural circuits, such as the insular cortex storing gut inflammation signals.
Reactivating these brain circuits can recreate specific peripheral inflammatory responses.

INSIGHT

Role of Microglia in Brain Health

Microglia are the brain's resident immune cells that help maintain and remodel neural circuits by pruning synapses.
These cells also regulate brain metabolism to maintain healthy neural environments beyond pathogen defense.

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Episode Summary: Dr. Michael Wheeler talks about neuroimmune interactions, exploring how the immune system and brain communicate, particularly through the blood-brain barrier and meninges; how chronic stress and inflammation can alter brain circuits, contributing to mood disorders like depression; how drugs like psilocybin and MDMA may reduce inflammation by modulating immune cells in the meninges, offering potential therapeutic benefits.

About the guest: Michael Wheeler, PhD is an Assistant Professor of Neurology at Harvard Medical School. His lab studies how immune responses influence behavior, mood disorders, and addiction.

Key Conversation Points:

The blood-brain barrier (BBB) is not as impermeable as once thought, allowing immune signals like cytokines to influence brain function even in healthy states.
Chronic stress can weaken the BBB, increasing inflammation and affecting mood-regulating circuits, potentially contributing to depression.
Microglia, the brain’s resident immune cells, help maintain neural circuits by pruning synapses and regulating metabolism.
Psychedelics like psilocybin and MDMA can reduce inflammation by prompting immune cells (monocytes) to leave the meninges, potentially via vascular effects.
These psychedelics may act in a context-specific “window,” requiring a dysregulated tissue state to exert anti-inflammatory effects, not as broad-spectrum anti-inflammatories.
Neuroinflammation may underlie some treatment-resistant depression cases, suggesting immunotherapy could complement traditional psychiatric treatments.
The brain encodes peripheral immune signals, like gut inflammation, in specific circuits, which can “remember” and recreate inflammatory responses.
Aging may naturally increase blood-brain barrier leakiness, heightening the brain's susceptibility to peripheral inflammation.
Future research aims to explore how psychedelics influence plasticity and their potential in treating inflammation-related diseases beyond psychiatry.

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